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PubMed1995

Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit.

The NMDA (N-methyl-D-aspartate) receptor channel is important for synaptic plasticity, which is thought to underlie learning, memory and development. The NMDA receptor channel is formed by at least two members of the glutamate receptor (GluR) channel subunit families, the GluR epsilon (NR2) and GluR zeta (NR1) subunit families. The four epsilon subunits are distinct in distribution, properties and regulation. On the basis of the Mg2+ sensitivity and expression patterns, we have proposed that the epsilon 1 (NR2A) and epsilon 2 (NR2B) subunits play a role in synaptic plasticity. Here we show that targeted disruption of the mouse epsilon 1 subunit gene resulted in significant reduction of the NMDA receptor channel current and long-term potentiation at the hippocampal CA1 synapses. The mutant mice also showed a moderate deficiency in spatial learning. These results support the notion that the NMDA receptor channel-dependent synaptic plasticity is the cellular basis of certain forms of learning.

Animals↗
PubMed2004

Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons.

The pathological significance of intracellular Abeta accumulation in vivo is not yet fully understood. To address this, we have studied transgenic rats expressing Alzheimer's-related transgenes that accumulate Abeta intraneuronally in the cerebral and hippocampal cortices but do not develop extracellular amyloid plaques. In these rats, the presence of intraneuronal Abeta is sufficient to provoke up-regulation of the phosphorylated form of extracellular-regulated kinase (ERK) 2 and its enzymatic activity in the hippocampus while no changes were observed in the activity or phosphorylation status of other putative tau kinases such as p38, glycogen synthase kinase 3, and cycline-dependent kinase 5. The increase in active phospho-ERK2 was accompanied by increased levels of tau phosphorylation at S396 and S404 ERK2 sites and a decrease in the phosphorylation of the CREB kinase p90RSK. In a water maze paradigm, male transgenic rats displayed a mild spatial learning deficit relative to control littermates. Our results suggest that in the absence of plaques, intraneuronal accumulation of Abeta peptide correlates with the initial steps in the tau-phosphorylation cascade, alterations in ERK2 signaling and impairment of higher CNS functions in male rats.

Amyloid beta-Peptides↗
PubMed2003

Spatial learning deficits induced by muscimol and CL218,872: lack of effect of prenatal malnutrition.

The sensitivity of prenatal protein malnourished rats to the amnestic properties of the direct GABAA receptor agonist muscimol and the selective benzodiazepine (BZ) receptor agonist, CL218,872, was studied in the male offspring of rats provided with a protein deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. At postnatal day 90, rats were tested during acquisition of the submerged platform version of the Morris water maze task using four systemic doses of muscimol (0.1, 0.3, 1.0 and 1.8 mg/kg i.p.) or three systemic doses of CL218,872 (1.0, 3.2, and 5.6 mg/kg i.p.). In a dose dependent manner both drugs impaired acquisition of the task and impaired accuracy of the search pattern on the probe trial (platform removed). However, neither drug dissociated the performance of the two nutritional groups. These data are important in light of previous findings of differential behavioral effects of the non-specific BZ agonist, chlordiazepoxide (CDP), on spatial learning and on drug discrimination in prenatally malnourished rats and in the context of previous findings of reduced sensitivity to the anxiolytic effects of non-specific BZ receptor agonists across a wide variety of models of malnutrition. The present findings also support the concept that prenatal malnutrition does not affect the global functioning of the GABAA receptor, but fundamentally alters the way in which a subset of GABAA receptors (i.e. those containing the alpha2, alpha3 and/or the alpha5 but not the alpha1 subunit) is modulated by BZs.

Animals↗
PubMed2002

The role of the laterodorsal nucleus of the thalamus in spatial learning and memory in the rat.

The anterior thalamic nuclei appear to play an important role in learning and memory. Connectionally and structurally, the lateral dorsal nucleus is similar to the anterior nuclei. This study tested the hypothesis that the laterodorsal thalamic nucleus (LD) also contributes to these functions. Adult Sprague-Dawley rats received bilateral ibotenic acid lesions of LD, and 2 weeks later the rats were tested in a repeated acquisition water maze task. The control groups displayed a short final escape latency and showed a preference for the correct quadrant in the probe trial. Rats with a lesion restricted to LD (LDL) were mildly impaired in the task, but rats with lesions that destroyed LD and also significantly (50%) damaged the adjacent anterior thalamic nuclei (LDL+) were severely impaired, displaying no improvement in performing the spatial task. In a second experiment, training in the same paradigm for 2 weeks resulted in improved final performance by LDL and control rats but not by LDL+ rats. These findings support the hypothesis that together with the anterior thalamic nuclei, LD plays a role in spatial learning and memory.

Animals↗
PubMed1994

Relation of spatial learning of rats in the Morris water maze task to the number of viable CA1 neurons following four-vessel occlusion.

Male Wistar rats were tested in the Morris water maze task 1 week after 6, 9, or 12 min of transient global ischemia. The 9-min and 12-min ischemia groups were significantly impaired in the acquisition and the reversal experiment. A systematic counting of CA1 neurons in the whole hippocampal formation revealed a unilateral number of CA1 neurons of 286,000 in the sham group, of which 2/3 were located in the dorsal hippocampus. The ischemia groups showed a significant decline in the number of dorsal CA1 neurons, whereas only the 12-min ischemia group showed a significant but minor decline (10%-15%) in the number of ventral CA1 neurons. A correlation analysis showed that the escape distance declined with increasing number of viable CA1 neurons, but poor correlation coefficients were obtained. Thus, some of the ischemic rats with even very few viable CA1 neurons in the dorsal hippocampus were capable of performing this spatial learning task at sham-group level.

Animals↗
PubMed2000

Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats.

Purpose: The present study investigated the effects of fluoxetine, a serotonin reuptake blocker, on behavioral deficits of rats subjected to transient focal cerebral ischemia. Methods: The right middle cerebral artery of rats was occluded for 120 min using the intraluminal filament method. Fluoxetine treatment (5 mg/kg, i.p.) was started 2 days after ischemia induction and treatment was continued for 10 days thereafter. Sensorimotor recovery was assessed using the limb-placing test and cognitive impairment was assessed using a water-maze test at the end of the experiment. Results: Fluoxetine treatment did not improve performance of ischemic rats in the limb-placing test. Nor was the ischemia-induced deficit in the water-maze test affected by fluoxetine. The infarct volumes in the cortex or striatum, determined after the experiment, were not different between ischemic groups. Conclusion: These results suggest that subchronic fluoxetine treatment following experimental focal cerebral ischemia is not detrimental to behavioral outcome, but it also does not enhance spontaneous sensorimotor recovery or attenuate spatial learning deficits.

Journal Article↗
PubMed1996

Spatial learning in rats exposed to acute ethanol intoxication on gestational day 8.

Pregnant Wistar rats were treated on gestational day 8 (GD 8) with two IP injections of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline. Offspring were tested in the water-maze task at 45 or 90 days of age. The escape latencies of rats trained with a submerged escape platform at a fixed location were similar between control and experimental rats. Analyses of responses on a probe trial carried out 10 days after the training period, revealed that 90-day-old females prenatally exposed to alcohol were less likely to swim in the target region. No differences were observed in this free-swim trial in 45- and 90-day-old male, and 45-day-old female animals. Binding studies of low-affinity GABAA sites in the hippocampus showed an increase in affinity of [3H]GABAA for their binding sites in 90-day-old female offspring prenatally intoxicated with ethanol. Our results demonstrate that acute intoxication with ethanol on GD 8 did not modify acquisition but impaired the retention of spatial learning only in adult female rats. It is possible that the impaired retention will be consequence of higher GABAA receptor affinity.

Alcoholic Intoxication↗
PubMed2003

Repetitive acute pain in infancy increases anxiety but does not alter spatial learning ability in juvenile mice.

We assessed the long-term behavioural effects of a single acute or repetitive inflammatory pain experienced during infancy. Groups of male and female CD1 mice were subjected to either an acute single pain, i.e. a tail clip or sham pain at P8, or acute repetitive pain in the form of needle pricks or sham pain from P8 to P14. All of the subjects were tested in the elevated plus maze at P30 and in the Morris Water Maze from P31 to P38. Mice in the acute single pain and sham groups did not differ on measures of anxiety in the plus maze. Mice in the repetitive pain group demonstrated significantly more anxious behaviours than controls in the elevated plus maze as they spent less time in the open arms, made fewer open arm entries, displayed fewer head dips and showed more stretch attend postures. There were no effects of single or repetitive pain treatments in the latency to find the hidden platform in the Morris Water Maze. Overall, these data suggest that acute repetitive pain experienced during infancy may increase anxiety later in life but it does not influence spatial learning as measured in the Morris Water Maze. The origin of the anxiogenic profile shown in the acute repetitive pain mice may be a result of changes in neural circuitry or context dependent learning and is currently under further investigation with this paradigm.

Acute Disease↗
PubMed2006

Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus.

Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later. Compared to sham-irradiated rats, the irradiated rats demonstrated impaired MWM performance. The relative levels of the NR1 and NR2A but not the NR2B subunits of the NMDA receptor were significantly higher in hippocampal CA1 of irradiated rats compared to control rats. No significant differences were detected for these NMDA subunits in CA3 or dentate gyrus. Further analysis of CA1 revealed that the relative levels of the GluR1 and GluR2 subunits of the AMPA receptor and synaptophysin were not altered by whole-brain irradiation. In summary, a clinically relevant regimen of fractionated whole-brain irradiation led to significant impairments in spatial learning and reference memory and alterations in the relative levels of subunits of the NMDA, but not the AMPA, receptors in hippocampal CA1. These findings suggest for the first time that radiation-induced cognitive impairments may be associated with alterations in glutamate receptor composition.

Animals↗
PubMed2000

Selectivity of the spatial learning deficit after lesions of the mammillary region in rats.

Rats with lesions of the mammillary region (MB-R) or a control group (C) were trained on a visual-spatial conditional associative learning task in which they had to learn to go to one of two locations depending on the particular visual cue presented on each trial; the rats approached the cues from different directions. The animals were subsequently tested on a spatial working memory task, the eight-arm radial maze. Rats with damage to the MB-R were able to acquire the conditional associative task at a rate comparable to that of the C animals. By contrast, lesions of the MB-R led to a severe impairment on the radial maze. The present finding of a dissociation between the effects of MB-R lesions on two different classes of behavior suggest that the spatial learning deficit following damage of this region may be specific to remembering one or more places over a given time but not the ability to form associations between visual and spatial stimuli.

Animals↗
PubMed2002

Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.

Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.

Animals↗
PubMedDate not supplied

Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice.

To define the physiological role of IP(3)3-kinase(A) in vivo, we have generated a mouse strain with a null mutation of the IP(3)3-kinase(A) locus by gene targeting. Homozygous mutant mice were fully viable, fertile, apparently normal, and did not show any morphological anomaly in brain sections. In the mutant brain, the IP4 level was significantly decreased whereas the IP3 level did not change, demonstrating a major role of IP(3)3-kinase(A) in the generation of IP4. Nevertheless, no significant difference was detected in the hippocampal neuronal cells of the wild-type and the mutant mice in the kinetics of Ca2+ regulation after glutamate stimulation. Electrophysiological analyses carried out in hippocampal slices showed that the mutation significantly enhanced the LTP in the hippocampal CA1 region, but had no effect on the LTP in dentate gyrus (DG). No difference was noted, however, between the mutant and the wild-type mice in the Morris water maze task. Our results indicate that IP(3)3-kinase(A) may play an important role in the regulation of LTP in hippocampal CA1 region through the generation of IP4, but the enhanced LTP in the hippocampal CA1 does not affect spatial learning and memory.

Animals↗
PubMed2005

The effects of chronic nicotine on spatial learning and bromodeoxyuridine incorporation into the dentate gyrus of the rat.

RATIONALE: Nicotine is reported to improve learning and memory in experimental animals. Improved learning and memory has also been related to increased neurogenesis in the dentate gyrus (DG) of the hippocampal formation. Surprisingly, recent studies suggest that self-administered nicotine depresses cell proliferation in the DG. OBJECTIVE: To test the hypothesis that the effects of nicotine on cell proliferation in the DG and learning and memory depend upon the nicotine dose administered. METHODS: Rats were chronically infused from subcutaneous osmotic mini pumps with nicotine (0.25 or 4 mg kg(-1) day(-1)) or the saline vehicle for 10 days. Half the rats in each treatment group were trained to locate a hidden platform in a water maze task on days 4-7; a probe trial was performed on day 8. The remaining rats remained in their home cages. The effects of nicotine and of training in the water maze task on cell genesis in the DG were determined by measuring 5-bromo-2'-deoxyuridine (BrDU) uptake using fluorescence immunohistochemistry. RESULTS: Training in the water maze task increased cell proliferation in the DG. Infusions of nicotine at 4 mg kg(-1) day(-1), but not 0.25 mg kg(-1) day(-1), decreased cell proliferation in both untrained animals and animals trained in the maze and impaired spatial learning. CONCLUSIONS: The data suggest that learning in the water maze task is impaired by higher doses of nicotine tested, and that this response may be related to reduced cell genesis in the DG.

Animals↗
PubMed1993

Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine.

Nimodipine levels were measured in blood and brain of rats implanted SC with sustained-release pellets of nimodipine (0, 10, 20, or 40 mg). Dose-dependent levels of nimodipine were detected in both plasma and brain. These results indicated the possible usefulness of these pellets in behavioral studies where long-term treatment is required. Therefore, the effects of chronic nimodipine, using 40-mg pellets, were examined on the performance of young, middle-aged, and aged rats in the Morris water maze. Following implantation of either nimodipine or placebo pellets, rats were trained for 6 days (three sessions/day) followed by 6 days of reversal training. During both initial and reversal training, every sixth trial was a probe trial. During initial training, there were clear age-related acquisition deficits in place training, with no effects of chronic nimodipine. Nimodipine did, however, enhance performance of rats during the first and second probe trials of reversal training. Time spent in the training quadrant by nimodipine-treated rats was approximately 30% longer on the first reversal probe and 35% longer on the second reversal probe than time spent in this quadrant by placebo-treated animals. These results indicate that chronic nimodipine enhances the performance of normal animals in reversal training on a spatial learning task.

Aging↗
PubMed1999

Effect of chronic nimodipine on spatial learning and on long-term potentiation.

The present study examined the effect of nimodipine on a reference memory task and on the induction and maintenance of long-term potentiation (LTP) in the hippocampal dentate gyrus. Young rats, subcutaneously implanted with either a 30 mg nimodipine or placebo pellet, were trained on the Barnes circular platform task. Retention was tested 15 days following acquisition. Following behavioural testing, recording and stimulating electrodes were implanted in the granule cell layer of the dentate gyrus and the perforant path, respectively. Pre-pellet baseline evoked potentials were collected. Nimodipine or placebo pellets were again subcutaneously implanted, according to the original groupings, and post-pellet baseline evoked potentials were obtained. LTP was then induced in the granule cell population by perforant path tetanization and the decay of LTP was followed for 15 days. Nimodipine significantly decreased the number of trials to reach both the acquisition and the retention criterion on the circular platform task, but did not alter granule cell excitability, LTP threshold, or the magnitude of LTP. Sustained nimodipine administration, however, increased the decay rate of LTP of the population spike, but did not affect the decay rate for LTP of the EPSP. No significant correlations were obtained between behavioural and electrophysiological measures. These results provide further evidence against a simple direct relationship between LTP and spatial learning.

Animals↗
PubMed2005

The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity.

Hippocampal synaptic plasticity is expressed to very different extents in distinct rat strains in vivo. This may correlate with differences in learning ability. We investigated whether the metabotropic glutamate receptor mGluR5 contributes to differences in long-term potentiation (LTP) and learning in freely moving hooded Lister (HL) and Wistar rats. High-frequency tetanization (HFT) generated robust CA1 LTP in Wistar rats (> 24 h) and incremental potentiation in HL rats. The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP; 1.8 microg), applied intracerebrally, impaired LTP from approximately 60 min onwards in Wistar and from 24 h in HL rats. HFT generated LTP in the dentate gyrus (DG) of Wistar rats (> 24 h), which was blocked by MPEP, and MPEP-resistant short-term depression in HL rats. Training for 10 days in an eight-arm radial maze revealed no working memory differences, but better reference memory performance in Wistar compared with HL rats. Daily application of MPEP (1.8 microg) impaired working and reference memory in Wistar rats. In HL rats, working memory was impaired but reference memory was unaffected. Western blot analysis revealed lower expression of mGluR5 in HL compared with Wistar rats. MGluR1 expression was equivalent. These data reveal striking mGluR5-dependent differences in spatial learning in different rat strains, which correlate to synaptic plasticity and mGluR5 expression levels.

Animals↗
PubMed1998

Baclofen infused in rat hippocampal formation impairs spatial learning.

Recent studies show that baclofen, a selective GABA(B) agonist, impairs different kinds of learning. In the present study we investigated the effect of microinfused baclofen into the hippocampus of male Wistar rats, on the performance in the Morris water maze. Rats of 8-10 weeks of age were implanted with cannulae aimed bilaterally at the hippocampal formation. Baclofen (1 microl of 0.2 mM, 2.0 mM, and 20.0 mM) or sterilized saline was microinfused 1 h before each daily session (3 trials/session, 1 session/day) for 4 days. On the fifth day, the animals did not receive drug or saline injections and the retention of the location of the escape platform was tested in a 30 s free swim trial. Results from the free swim trial indicate that the doses of baclofen used during training affected the ability of the rats to swim to the target quadrant. Although no significant difference compared with the saline group was observed, the experimental rats showed a more generalized swim trajectory in the area of the target and both adjacent quadrants. Moreover, 1 microl of 20.0 mM baclofen also impaired the acquisition. We suggest that baclofen has an impairing action on spatial learning, although more studies should be conducted to reach a more precise conclusion.

Animals↗
PubMed2006

Impaired long-term depression in P2X3 deficient mice is not associated with a spatial learning deficit.

The hippocampus is a brain region critical for learning and memory processes believed to result from long-lasting changes in the function and structure of synapses. Recent findings suggest that ATP functions as a neurotransmitter or neuromodulator in the mammalian brain, where it activates several different types of ionotropic and G protein-coupled ATP receptors that transduce calcium signals. However, the roles of specific ATP receptors in synaptic plasticity have not been established. Here we show that mice lacking the P2X3 ATP receptor (P2X3KO mice) exhibit abnormalities in hippocampal synaptic plasticity that can be restored by pharmacological modification of calcium-sensitive kinase and phosphatase activities. Calcium imaging studies revealed an attenuated calcium response to ATP in hippocampal neurons from P2X3KO mice. Basal synaptic transmission, paired-pulse facilitation and long-term potentiation are normal at synapses in hippocampal slices from P2X3KO. However, long-term depression is severely impaired at CA1, CA3 and dentate gyrus synapses. Long-term depression can be partially rescued in slices treated with a protein phosphatase 1-2 A activator or by postsynaptic inhibition of calcium/calmodulin-dependent protein kinase II. Despite the deficit in hippocampal long-term depression, P2X3KO mice performed normally in water maze tests of spatial learning, suggesting that long-term depression is not critical for this type of hippocampus-dependent learning and memory.

Adenosine Triphosphate↗